tbuckley/cabot-search huggingface dataset:
Abstract 6213: Disruption of XPF function by HPV promotes alternative end joining and sensitivity to cisplatin in HNSCC
Authors: Qi Liu, Nan Zuo, Lin Ma, Lanlan Wei
Journal: Cancer Research (2023)

Abstract Human papillomavirus (HPV) positive head and neck squamous cell carcinoma (HNSCC) usually show a tremendous better clinical outcome compared to their HPV-negative counterparts. Although the HPV associated survival advantage is partially explained by the enhanced cisplatin sensitivity in HNSCC (Clin Ca Res 2018, 24(23): 6001), the underlying mechanisms are still poorly elucidated. Cisplatin causes DNA interstrand crosslinks (ICLs) that requires Fanconi anemia (FA) pathway for DNA repair. Consistently, our study showed that HPV-positive HNSCC cells exhibited a FA defective cellular phenotype. In clonogenic cell survival assay, 1h treatment with 5μM cisplatin eliminated approximately 56.7% more HPV-positive HNSCC cells than HPV-negative ones. Furthermore, HPV-positive cells treated with cisplatin showed prolonged G2/M cell cycle arrest and more 53BP1 foci, indicating profound deficiency in repairing ICLs. Consistent with these findings, increased aberrant chromosome formation was observed in HPV-positive cells following Mitomycin C treatment. In order to reveal the mechanism, we further interrogated HPV-labeled HNSCC samples in TCGA database, and identified XPF, an endonuclease protein in FA pathway, was downregulated in HPV-positive HNSCC. Further analysis of cellular and clinical samples confirmed that both mRNA and protein expressions of XPF were significantly lower in HPV-positive HNSCC (P&amp;lt;0.001). To test the importance of XPF in HPV-induced cisplatin sensitivity, we performed a cell viability assay, and found that knock-down of XPF increased the effects of cisplatin on HPV-negative HNSCC by 39.54% (± 4.42%), while no significant change was observed in HPV-positive HNSCC (P&amp;gt;0.05). Notably, inhibition of XPF function by a small molecule inhibitor recapitulated the effect of HPV, resulted in enhanced error-prone DNA repair with alternative end-joining (alt-EJ). In a probe-based ddPCR assay, XPF inhibition increased 32.02% (± 5.80%, P&amp;lt;0.001) alt-EJ events in HPV-negative HNSCC cells, while little difference was detected in HPV-positive cells. Thus, we speculated that combined inhibition of XPF and alt-EJ may improve clinical outcome in the difficult-to-treat, HPV-negative HNSCC, which worth further research efforts. Citation Format: Qi Liu, Nan Zuo, Lin Ma, Lanlan Wei. Disruption of XPF function by HPV promotes alternative end joining and sensitivity to cisplatin in HNSCC. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6213.
Abstract 2698: Improved calcium phosphate delivery system cNaD to aim clinical application
Authors: Hirofumi Yamamoto
Journal: Cancer Research (2023)

Abstract Super carbonate apatite (sCA) nanoparticle is a superb calcium phosphate delivery system for miRNA and siRNA to tumors (PlosOne 2015). We reported that sCA delivered efficiently siRNA for survivin and PTBP as well as miR-340 (Mol Cancer Ther 2015, 2015) to colon tumors implanted into nude mice. MiR-4689 and miR-29b-1-5p suppressed KRAS mutated colon cancer cells (Mol Ther NA2015, 2018) and miR-302 and miR-369 realized in vivo cancer reprograming (PlosOne 2015). In every case the RNA function was fully realized. Moreover, effect of influenza vaccination was augmented by sCA plus CpG nucleic acid (NA) (Frontiers in Immunol 2018). sCA coupled with miR-29a or miR-29b prevented the DSS (dextran sodium sulfate)-induced inflammatory bowel disease (Mol Ther NA2018). We also applied the sCA-ICG complex to minimally invasive treatment of photodynamic therapy (Mol Cancer Ther 2018). Following these outstanding findings, we tried and succeeded to establish a clinically available novel calcium phosphate delivery system, named cNaD, which controls the nano-particle size and avoids accumulation in normal organs including liver and spleen. It is characterized by its ability to efficiently deliver siRNA and microRNA to cancers and provided prominent therapeutic effect in various mouse models. Safety test has been accomplished in rats and monkeys based on GLP standards. Also, the scale-up manufacturing system &amp;gt;1000 folds has been attained. Our cNaD system will accelerate the development of NA medicine in the world. Citation Format: Hirofumi Yamamoto. Improved calcium phosphate delivery system cNaD to aim clinical application [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2698.
Abstract 105: Gene expression heterogeneity reveals therapeutic targets and novel regulators of metastasis
Authors: Dongbo Yang, Christopher Dann, Andrea Valdespino, Lydia Robinson-Mailman, Mengjie Chen, Gábor Balázsi, Sebastian Pott, Marsha Rich Rosner
Journal: Cancer Research (2023)

Abstract Tumor cell heterogeneity has been implicated in metastatic progression of solid tumors such as triple-negative breast cancer (TNBC), leading to resistance and recurrence. We hypothesize that genes with low cell-to-cell transcriptional variability are more effective therapeutic targets, and use of variability as a metric will identify new metastatic regulators. Using single cell RNA sequencing, we demonstrate that the metastasis suppressor Raf Kinase Inhibitory Protein (RKIP/PEBP1) reduced overall transcriptional heterogeneity in TNBC xenograft tumors including oxidative phosphorylation genes. Consistent with a dependence on respiratory genes, metformin inhibited growth of RKIP-expressing but not RKIP-deficient tumors. Among genes with reduced transcriptional variability and increased mean in response to RKIP, we identified KMT5C as a novel epigenetic metastasis suppressor in TNBC. Taken together, these results indicate that analysis of gene expression variability along with mean can lead to effective target selection and provides an alternative strategy for identifying novel regulators of metastasis. Citation Format: Dongbo Yang, Christopher Dann, Andrea Valdespino, Lydia Robinson-Mailman, Mengjie Chen, Gábor Balázsi, Sebastian Pott, Marsha Rich Rosner. Gene expression heterogeneity reveals therapeutic targets and novel regulators of metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 105.
Abstract 5055: Targeting BRAFV600E/NRASQ61K-melanoma brain metastases by pharmacological intervention modulating ER/redox stress and EMT
Authors: Jana Jandova, Sophia L. Park, Jeremy A. Snell, Georg T. Wondrak
Journal: Cancer Research (2023)

Abstract Intracranial melanoma metastases originating from peripheral malignancy remain a frequent clinical condition with unsatisfactory pharmacological options. After screening a focused library of clinical artemisinin-combination therapeutic (ACT) antimalarials with established brain availability, we report here that an oral antimalarial regimen {(R,S)/(S,R)-[2,8-bis(trifluoromethyl)quinolin-4-yl]-piperidin-2-ylmethanol; BQPM} blocks (i) melanoma cell invasiveness and EMT-related gene expression and (ii) tumor growth in a bioluminescent murine model of BRAFi-resistant intracranial melanoma. First, we examined apoptotic elimination of cultured malignant melanoma cell lines, also examining feasibility of overcoming BRAFi-resistance comparing isogenic melanoma cells that differ only by NRAS mutational status (BRAFi-sensitive A375-BRAFV600E/NRASQ61 versus BRAFi-resistant A375-BRAFV600E/NRASQ61K). Among ACT antimalarials tested, BQPM was the only apoptogenic agent causing melanoma cell death at low micromolar concentrations. Comparative gene expression-array analysis (A375-BRAFV600E/NRASQ61 versus A375-BRAFV600E/NRASQ61K) revealed that BQPM is a dual inducer of endoplasmic reticulum (ER) and redox stress responses that precede BQPM-induced loss of viability. Moreover, we observed that BQPM treatment blocked EMT-related gene expression and phenotypic invasiveness in both BRAFi-sensitive and -resistant human cell lines, observable also in murine CNS-tropic Ret-melanoma cells. These data (combined with clinical evidence that documents brain availability of BQPM) suggest that blockade of brain metastasis and inhibition of intracranial tumor growth, even if BRAFi-resistant, can be achieved using BQPM as a repurposed ACT-antimalarial. Citation Format: Jana Jandova, Sophia L. Park, Jeremy A. Snell, Georg T. Wondrak. Targeting BRAFV600E/NRASQ61K-melanoma brain metastases by pharmacological intervention modulating ER/redox stress and EMT. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5055.
Abstract 6134: Exploiting the oncogenic state of colorectal cancer for therapeutic development
Authors: Felipe de Sousa e Melo
Journal: Cancer Research (2023)

Abstract Over the past two decades, only incremental progresses have been made in the therapeutic management of colorectal cancer (CRC). This is in part attributed to the fact that the Wnt pathway, the oncogenic pathway that initiates the transformation of CRC and sustains tumor maintenance, has been largely undruggable. While most efforts targeting Wnt signaling have revolved around interfering with Wnt target genes that regulate cell growth, we turned our attention to a subset of genes encoding for negative regulators of the pathway. Of particular interest are the cell-surface E3 ubiquitin ligases, ring finger protein 43 (RNF43) and ZNRF3, two known negative regulators of Wnt signaling that promote the turnover of Wnt receptors Frizzled/low-density lipoprotein receptor-related proteins (FZD/LRPs) via ubiquitination-mediated degradation. Given their exposed extracellular domains (ECDs), we set out to explore whether this intrinsic cellular degradative machinery could be repurposed for an antibody-based targeted protein degradation platform. More specifically, we have devised a technology that exploits the elevated expression of ZNRF3 and RNF43 in colon cancer by generating bispecific antibodies that can tether these E3 ubiquitin ligases to a variety of cell surface receptors to promote tumor receptor degradation. Most notably, these antibody degraders are highly active in vivo and can degrade receptors in a tumor specific manner while sparing normal tissues. This platform, that we have been dubbed Proteolysis Targeting Antibodies (PROTABs) describes a strategy for the rapid development of potent, bioavailable and tissue-selective degraders of cell-surface proteins. Citation Format: Felipe de Sousa e Melo. Exploiting the oncogenic state of colorectal cancer for therapeutic development. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6134.
Abstract 4773: DEAD Box 1 (DDX1) protects its RNA targets in cells exposed to oxidative stress
Authors: Mansi Garg, Roseline Godbout
Journal: Cancer Research (2023)

Abstract DEAD box 1 (DDX1) belongs to the family of RNA helicases involved in all aspects of RNA metabolism, from transcription to transport, expression, and decay. DDX1 is overexpressed in a subset of retinoblastoma, neuroblastoma, and breast cancers. In breast cancer, the overexpression and cytoplasmic localization of DDX1 is correlated with poor prognosis. Cancer cells often exhibit high metabolic rates which can lead to genomic instability, oxidative stress, and endoplasmic stress. DDX1 is known to play a role in resolving genotoxic stress by participating in DNA double-strand break (DSB) repair. We propose that DDX1 also plays a key role as a stress response regulator in cells undergoing oxidative stress. When cells are exposed to oxidative stress, DDX1 is recruited to cytoplasmic stress granules (SGs). Although the exact function of SGs remains elusive, it is generally believed that tightly controlled SG assembly and disassembly are important for cell survival under stress. We found that while DDX1 is dispensable for SG assembly, depletion of DDX1 leads to impaired SG disassembly and hence, delayed stress recovery. Thus, DDX1 may play a role in stress resolution after the removal of stress conditions. To further understand the role of DDX1 in stress resolution, we performed RNA-immunoprecipitation followed by next-generation sequencing and identified DDX1-bound RNAs under normal and oxidative stress conditions. We found enhanced binding of DDX1 to its RNA targets in the presence of oxidative stress. Furthermore, we observed that DDX1 protects its target RNAs from degradation in the cytoplasm of cells undergoing oxidative stress. This RNA protection after stress exposure was more prominent in DDX1-overexpressing neuroblastoma cells, possibly explaining the faster stress recovery observed in these cells. Taken together, our results suggest that DDX1 plays a role in protecting cells from oxidative stress. This study may shed light on our understanding of cancer cell resistance to anticancer therapies. Citation Format: Mansi Garg, Roseline Godbout. DEAD Box 1 (DDX1) protects its RNA targets in cells exposed to oxidative stress. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4773.
Impact of an NCCN-Compliant Multidisciplinary Conference on Treatment Decisions for Localized Prostate Cancer
Authors: Ahmed A. Hussein, Umar Iqbal, Zhe Jing, Yousuf Ramahi, Holly Houenstein, Stephanie Newman, Blake Peterson, Katarina Krajacic, Adeena Samoni, Bo Xu, Norbert Sule, Gissou Azabdaftari, Eric C. Kauffman, James L. Mohler, Michael Kuettel, Khurshid A. Guru
Journal: Journal of the National Comprehensive Cancer Network (2023)

We sought to investigate the impact of an NCCN-compliant multidisciplinary conference on treatment decisions of patients with localized prostate cancer.A retrospective review of our quality assurance localized prostate cancer database was performed. All patients with localized prostate cancer who sought a second opinion at Roswell Park Comprehensive Cancer Center between 2009 and 2019 were presented to the multidisciplinary Localized Prostate Cancer Conference (LPCC) that includes urologists, radiation oncologists, pathologists, and patient advocates. Multivariable regression models were fit to evaluate variables associated with concordance between community recommendations, LPCC recommendations, and treatment received by patients.A total of 1,164 patients were identified, of whom 26% had NCCN very low-/low-risk, 27% had favorable intermediate-risk, 25% had unfavorable intermediate-risk, and 22% had high-/very high-risk prostate cancer. Pathology changed in 11% of patients after genitourinary pathologist review, which caused disease reclassification in 9%. Concordance between community and LPCC recommendations occurred in 78%, with lowest concordance for androgen deprivation therapy (21%) and radiotherapy (53%). Concordance between community recommendations and treatment received occurred in 65%, with lowest concordance for androgen deprivation therapy and radiotherapy; among those who were recommended radiotherapy as the only option by their community urologist, only 26% received it. Concordance between LPCC recommendations and treatment received occurred in 92%.Community recommendations differed from the multidisciplinary NCCN-compliant recommendations in 22% of patients, primarily for radiotherapy. Multidisciplinary recommendations matched the treatment received in 92% of patients compared with 65% for community recommendations.
Abstract 455: Development of an antibody-drug conjugate panel targeting high grade serous ovarian cancer
Authors: Ruisi Fu, Hantao Lou, Ning Wang, Dongnan Yan, Clara Tresserras-Segura, Haonan Lu, Eric Aboagye
Journal: Cancer Research (2023)

Abstract Antibody drug conjugate (ADC) is a novel class of therapeutic agent which recently showed great success in both solid tumour and blood cancer. ADCs deliver potent cytotoxic payloads to tumour via cancer specific monoclonal antibodies. A few ADCs are currently evaluated in clinical trials for high grade serous ovarian cancer (HGSOC). However, most of them target FOLR1-alpha, a conventional HGSOC target which also expresses in vital organs including lungs. Thus, it is desirable to discover more specific antigen targets, and these new targets will be the foundation for the next-generation ADC for HGSOC.We propose that ovarian tumour specificity of an ADC target could contributed by three factors: 1. Lineage (e.g. fallopian tube marker FOLR1); 2. DNA amplification (e.g. ERBB2); 3. Other carcinogenesis process including epigenetic reprogramming. Then, by combining the GTEX, TCGA dataset with our own WES, long-reads RNA-sequencing and Mass spectrometry-based proteomics cohort, an array of differentially expressed genes in HGSOC tumours are identified. Out of over 50 candidates, two most promising targets are chosen for monoclonal antibodies (mAbs) production and subsequent ADC development. First, the affinity and specificity of the mAbs were confirmed by ELISA, flow cytometry and immunofluorescence. The cellular internalisation characteristics of these antibodies are confirmed by a fluorescence-based assay. Then, ADCs for these two targets are produced by conjugating monomethyl auristatin E payload to the mAbs via a cleavable linker. Finally, both ADCs show highly target-specific and sub-nanomolar cytotoxicity in model ovarian cancer cell lines. In conclusion, we identify a panel of HGSOC-specific ADC targets and develop two ADCs candidates for further pre-clinical and clinical investigations. Citation Format: Ruisi Fu, Hantao Lou, Ning Wang, Dongnan Yan, Clara Tresserras-Segura, Haonan Lu, Eric Aboagye. Development of an antibody-drug conjugate panel targeting high grade serous ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 455.
Abstract 4607: TRPS1 inhibits angiogenesis in triple negative breast cancer down regulating JAG1 and TYMP genes involved in angiogenesis pathways
Authors: Liliana Guzman
Journal: Cancer Research (2023)

Abstract Background. Triple-negative breast cancer (TNBC), the most difficult subtype to treat, is defined as estrogen receptor, HER2, and progesterone receptor negative. TNBC constitutes 10-20% of all breast cancer and has a higher rate of distal recurrence and a poorer prognosis than other breast cancer subtypes. Less than 30% of women with metastatic TNBC survive 5 years and almost all die from their disease despite adjuvant chemotherapy. Angiogenesis is a critical factor in the development of tumors and metastases in numerous cancers. Clinical trials with anti-angiogenic drugs showed to be inadequate, with moderate response rates and insignificant survival gains for patients. To understand the genetic forces involved in TNBC, we performed a transposon mutagenesis screen in Pten mutant mice that identified several candidate trunk drivers and progression genes. A major finding of our screen was the discovery and functional validation of, Trichorhinophalangeal syndrome type 1 (TRPS1), a GATA-like transcription factor, which functions as a transcriptional repressor or activator, depending on cell type, stage of development, or pathological conditions. Based on this data, we explored the role of TRPS1 in angiogenesis. Methods and Results. Tube formation and sprouting assays were performed using overexpression and inactivation of TRPS1 in MDA-MD-231 and HCC70 cells, respectively. Interestingly, inactivation of TRPS1 expression accelerates tube formation structures compared to the vector control as well as cell branching in the sprouting assay. Overexpression of TRPS1 prevents tubing and branching formation in vitro assays. Moreover, immunohistochemistry staining of CD31 detected a reduced number of blood vessels in MDA-MB-231 tumor xenografts overexpressing TRPS1, and an increase of angiogenic vasculature in HCC70 TRPS1-shRNA tumor xenografts. In vitro and in vivo assays demonstrate the role of TRPS1 in tumor angiogenesis. Furthermore, human ChIP qPCR angiogenesis array identified 10 top candidate genes potentially regulated by TRPS1 transcription factor. Of these candidates, JAG1 and TYMP showed to have a higher fold enrichment compared to other angiogenic related genes. Finally, we validated its direct functional binding by using luciferase reporter assay, such demonstrated that TRPS1 is a direct transcriptional regulator of JAG1 and TYMP. Conclusion. TRPS1 is a tumor suppressor involved in the mechanisms regulating tumor angiogenesis by repressing the expression of JAG1 and TYMP genes in TNBC. Citation Format: Liliana Guzman. TRPS1 inhibits angiogenesis in triple negative breast cancer down regulating JAG1 and TYMP genes involved in angiogenesis pathways. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4607.